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Primary radiotherapy treatment is preferred for squamous cell carcinomas in the head and neck region (HNSCC) owing to the preservation of anatomical structures and function. The delineation of treatment volumes, particularly the expansion from the gross tumour volume (GTV) to the high-dose clinical target volume (CTV1), is critical in radiotherapy planning. Historically, the choice of margin size for GTV-CTV1 has varied between different treatment centres in Denmark from zero to over 10 millimetres or could encompass the whole organ (volume) where the tumour is located. Therefore, the first DAHANCA IMRT guidelines could be referred to as volumetric-based. In 2013, national consensus guidelines were introduced by the Danish Head and Neck Cancer Group (DAHANCA), recommending an isotropic margin of five millimetres corrected only for air or natural anatomical barriers resulting in a more uniform geometrical margin. With over a decade of experience in applying geometrically-based GTV-CTV1 guidelines, the primary aim of this study was to assess whether the implementation of the guidelines in 2013 led to improved consistency in CTV1 volumes across different treatment centres. Additionally, we analysed whether changes in GTV-CTV1 margins moving from volumetric to geometric guidelines impacted 3-year local tumour control and local recurrence pattern in patients treated three years before and three years after implementation of the geometrical guidelines. The cohort consisted of 1,948 patients diagnosed with oro-/hypopharyngeal and laryngeal squamous cell carcinomas across three national treatment centres. The patients underwent definitive intensity-modulated radiotherapy (IMRT) in 2010-2012 when volumetric guidelines were used, and in 2013-2015, when geometric guidelines were adopted. The GTV-CTV1 margins were quantitatively assessed by calculating the median surface distance from the primary GTV to CTV1. Three-year local control (LC) rates were determined, and local recurrence patterns were examined (Figure 1) using a centre of mass (COM) analysis. Hazard ratios and corresponding 90% CIs were calculated using the Cox proportional hazard model to identify factors that influenced local tumour control. [Display omitted] The transition from volumetric to geometric guidelines substantially reduced median GTV-CTV1 margins, declining from a median of 9.0 mm (IQR 0.0-9.7) to 4.7 mm (IQR 4.0-5.5). Importantly, adopting geometric guidelines led to increased consistency in CTV1 volumes between treatment centres. Median CTV1 changed from 76 to 61 cm3 for Centre1, from 28 to 53 cm3 for Centre2, and from 42 to 62 cm3 for Centre3 for the periods 2010-2012 and 2013-2015, respectively. The three-year LC rates exhibited a notable trend towards improvement, increasing from 0.84 to 0.87, although statistical significance was not reached (p=0.06). Cox regression analysis indicated that factors such as sex (female), tumour site (HPV p16+ oropharyngeal), T stage (T1-2), treatment schedule (6 or 10 fractions per week), and the administration of nimorazole and chemotherapy were associated with superior three-year LC. At the same time, GTV-CTV1 margin size did not appear to influence local control significantly (Figure 2). [Display omitted] Out of 146 radiology-verified local recurrences (LR), 102 (70%) were inside the CTV1. 45 (63%) and 57 (76%) LRs were inside CTV1 in 2010-2012 and 2013-2015, respectively. The LRs were covered by the 95% isodose in 75% in 2010-2012 and 91% in 2013-2015. The implementation of geometrically-based GTV-CTV1 margins resulted in reduced variation in treatment volumes across 3 different centres. Although our analysis did not demonstrate a direct impact of GTV-CTV1 margin size on local tumour control, a promising trend towards improved local control was observed in the newest cohort. Most recurrences occurred within CTV1 and were encompassed by the prescribed dose. A relevant next step could involve randomised trials comparing standard radiotherapy protocols with reduced margins and escalated doses to CTV1, further exploring the potential benefits of geometrically-based treatment strategies. [ABSTRACT FROM AUTHOR]

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The aim in radiotherapy treatment planning is to have sufficient target coverage and as low a dose to the Organs at Risk (OARs) as possible, adhering to the relevant guidelines. A high and consistent radiotherapy plan quality is vital when treatment plans are used as the foundation for patient selection in clinical trials. Proton therapy, being a substantially newer treatment modality than conventional photon therapy, is at risk of having a steeper learning curve in treatment planning. This inequality is important to investigate in a clinical study comparing the two, as this could influence the trial results. This study aims to evaluate the development of radiotherapy treatment plan quality for head and neck cancer patients receiving photon and proton therapy over time in the context of the DAHANCA 35 trial. From May 2019 to June 2023,189 patients were included in the ongoing DAHANCA 35 trial, with 63 patients in the pilot phase and 126 in the subsequent randomisation phase. In the pilot phase, all included patients were offered proton treatment, and in the randomisation phase, patients were randomised 1:2 (photon:proton). Patients were first seen at a local treatment centre, where a photon and comparative proton plan were prepared. If patients were offered proton treatment, a new clinical proton plan was made at the proton treatment centre and subsequently used for treatment. This study analysed 189 photon plans, 189 comparative proton plans, and 140 clinical proton plans. The treatment plans were prepared conforming to the DAHANCA guidelines [1] to ensure the clinical relevance of all treatment plans The plan quality was assessed separately for photon plans, comparative proton plans, and clinical proton plans in three time intervals. The mean dose was investigated individually for 13 OARs relevant for head and neck cancer: oesophagus, glottic larynx, supraglottic larynx, mandible, extended oral cavity, left and right parotid glands, upper-, middle-, and lower pharyngeal constrictor muscles, left and right submandibular glands, and thyroid gland. Furthermore, treatment plan quality was analysed using a new metric called Normalised Toxicity Index (NTI), calculated as a normalised average of the mean dose to the OARs compared to the threshold mean dose recommended by the DAHANCA guidelines. An NTI > 1 indicated that the OARs, on average, received a dose higher than the recommended thresholds, and an NTI < 1 indicated that the OARs received a dose below the thresholds. Hence, a lower NTI indicated better plan quality concerning OAR doses. The Kruskal-Wallis test was used to investigate a potential difference in the intervals for mean dose and NTI for each treatment type. The significance level was Bonferroni adjusted to account for multiple testing. The three time intervals were defined with 63 patients in the pilot phase constituting one interval (Pilot phase), the subsequent 64 patients from the randomisation phase in the next interval (Randomisation 1), and the remaining 62 patients from the randomisation phase in the third interval (Randomisation 2). The periods were 22 months for the Pilot phase, 19 months for Randomisation 1, and 14 months for Randomisation 2. Across the 13 OARs, the mean dose to individual OARs did not show a general time-dependent change, except for the right parotid gland in the clinical proton plans. Figure 1 shows a box plot with samples overlaid for the mean dose to the extended oral cavity as an example of the OARs. [Display omitted] The NTI was not significantly different for the photon plans, comparative proton plans, and clinical proton plans in the three consecutive intervals, as shown in Figure 2. The median NTI for the clinical proton plans was 0.88 (interquartile range [0.70,1.00]) for the Pilot phase, 0.83 [0.75,0.89] for Randomization 1, and 0.79 [0.67,0.98] for Randomization 2. The plan quality of the clinical proton plans appears stable from this new NTI metric. [Display omitted] The analyses conducted in this study did not show a general time-dependent change in plan quality in any of the three types of plans. This could be caused by the nationally developed proton treatment planning template. A stable treatment plan quality can help ensure a consistent selection for clinical trials, thus providing transparency for analysis of the outcome of the trials. The plan quality will continuously be followed to ensure consistency. [ABSTRACT FROM AUTHOR]

• OS of larynx cancer patients treated at Odense DK, Manchester UK and Liverpool AUS is driven by tumour volume and PS. • Federated learning can be used to create survival models without patient-sensitive data leaving the individual institutions. • The baseline hazards of the three institutions are similar, indicating the GTV volume and PS explain the cohort differences. • Smoking during treatment has the same risk profile as a ten year older patient not smoking. Federated learning has the potential to perfrom analysis on decentralised data; however, there are some obstacles to survival analyses as there is a risk of data leakage. This study demonstrates how to perform a stratified Cox regression survival analysis specifically designed to avoid data leakage using federated learning on larynx cancer patients from centres in three different countries. Data were obtained from 1821 larynx cancer patients treated with radiotherapy in three centres. Tumour volume was available for all 786 of the included patients. Parameter selection among eleven clinical and radiotherapy parameters were performed using best subset selection and cross-validation through the federated learning system, AusCAT. After parameter selection, β regression coefficients were estimated using bootstrap. Calibration plots were generated at 2 and 5-years survival, and inner and outer risk groups' Kaplan-Meier curves were compared to the Cox model prediction. The best performing Cox model included log(GTV), performance status, age, smoking, haemoglobin and N-classification; however, the simplest model with similar statistical prediction power included log(GTV) and performance status only. The Harrell C-indices for the simplest model were for Odense, Christie and Liverpool 0.75[0.71–0.78], 0.65[0.59–0.71], and 0.69[0.59–0.77], respectively. The values are slightly higher for the full model with C-index 0.77[0.74–0.80], 0.67[0.62–0.73] and 0.71[0.61–0.80], respectively. Smoking during treatment has the same hazard as a ten-years older nonsmoking patient. Without any patient-specific data leaving the hospitals, a stratified Cox regression model based on data from centres in three countries was developed without data leakage risks. The overall survival model is primarily driven by tumour volume and performance status. [ABSTRACT FROM AUTHOR]